Primary Open-Angle Glaucoma (POAG), the leading cause of blindness in the United States, is characterized by a progressive loss of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) is a major risk factor for RGC loss in glaucoma, but the mechanisms underlying IOP-mediated RGC loss are unclear. This application will test the hypothesis that proteases, tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), up-regulated by elevated IOP cause RGC loss and inhibition of these proteases prevents IOP-mediated RGC loss. This hypothesis will be tested through the following two specific aims by employing a well-established animal model for POAG. Aim 1 will determine whether the degree or the duration of elevated IOP up-regulates tPA and uPA. After inducing IOP elevation in brown Norway rats, protease levels will be determined by quantitative assays. Aim 2 will determine whether inhibition of tPA and uPA synthesis prevents IOP-mediated RGC loss. After inducing elevated IOP and inhibiting synthesis or proteolytic activity of proteases, RGC loss will be determined by retrograde labeling. Completion of the proposed studies will advance our understanding of the mechanisms underlying pressure-mediated ganglion cell loss in glaucoma and may lead to the development of therapeutic strategies to attenuate RGC loss in POAG patients.